The epidemic of HIV and syphilis and the correlation with substance abuse among men who have sex with men in China: A systematic review and meta-analysis

Background In China, the HIV/AIDS epidemic among men who have sex with men (MSM) has been expanding in recent years. Substance abuse in MSM was not well studied as the independent risk factor for HIV and syphilis infection and other sexually transmitted diseases. The present review aimed to determine the correlation between HIV/Syphilis infections and substance abuse and other sexual risk behaviors among MSM. Methods We conducted a comprehensive search of PubMed, Web of Science, Embase, Scopus, Chinese National Knowledge Infrastructure, Chinese Wanfang Data, and VIP Chinese Journal Database for relevant articles of quantitative studies published between 2010 and May 31, 2022. Meta-analysis was performed using R software. Pooled estimated of the association-odds ratio, with 95% confidence intervals were calculated using random-effects models stratified by study design. Q statistics and I2 were used to measure the heterogeneity. Results Our meta-analysis included 61,719 Chinese MSM from 52 eligible studies. The pooled HIV prevalence rate among substance-abusing MSM was 10.0% (95% CI = 0.08–0.13). Substance abusers were more likely to have a higher prevalence of HIV (OR = 1.59) and syphilis (OR = 1.48) infections than non-substance abusers. Substance abusers were also more likely to seek sexual partners through the internet or social media applications (OR = 1.63), engage in unprotected anal intercourse (UAI) (OR = 1.69), group sex (OR = 2.78), and engage in commercial intercourse (OR = 2.04) compared to non-users. Regarding testing behaviors, substance abusers had a higher proportion of HIV or STI testing in their lifetime (OR = 1.70) compared with non-substance abusers (p < 0.05). They were also more likely to have had more sexual partners (≥2; OR = 2.31) and more likely to have consumed alcohol (OR = 1.49) in the past 6 months. Conclusions Our study shows the correlation between substance abuse and HIV/Syphilis infection. Eliminating disparities in HIV/Syphilis infection among substance abusing men who have sex with men (MSM) can be achieved if the Chinese government and public health sectors could provide targeted knowledge popularization and diagnosis interventions among high-risk populations.


. Introduction
In China, the HIV/AIDS epidemic is increasing among men who have sex with men (MSM). By the end of 2020, the estimated number of people living with HIV was 2.1 million worldwide, with homosexual transmission accounting for 45.0% of reported HIV/AIDS cases (1). The HIV epidemic has exacted a severe toll on MSM, with HIV infections from 9.1% in 2009 to 23.3% in 2020 (2). In addition, the prevalence of HIV and syphilis co-infection has increased from 8% (Mexico, 2010(Mexico, -2018 to 25% (Turkey, 2013) (3,4). Previous studies have found that syphilis infections could potentially facilitate HIV transmission and increase the likelihood of acquiring HIV (5). The increasing HIV/AIDS epidemic among MSM is undoubtedly a major public health problem. Therefore, clarifying the risk factors associated with HIV acquisition among Chinese MSM is urgently needed to HIV prevention and intervention strategies.
Similarly, the global rates of substance abuse among men who have sex with men have increased dramatically. Evidence from European countries and China suggests that methamphetamine and ecstasy are the most popular drugs used by MSM in the past years (4)(5)(6). A recent study among 3,588 number of participants that explored drug use problems found that the use of nitrite inhalers have overtaken methamphetamine as the most popular substance abused among MSM (7). Chinese MSM has increasingly purchased poppers, and the proportion of poppers used among MSM was 24% in 2020 (8,9). The recreational use of drugs like rush poppers are more likely to be associated with sex and may thus be linked to the transmission of HIV and other sexually transmitted infections (STI).
On the one hand, drugs like meth/amphetamine, are often used to increase sexual desire and facilitate sexual experimentation (10). Rush popper may reduce pain by dilating capillaries and relaxing anal sphincters, increasing sexual confidence. However, substance abuse has both physiological and psychological effects on users. It may facilitate risky sexual practices, such as unprotected anal intercourse (UAI), thereby potentially increasing the risk of HIV and STI transmission (11)(12)(13)(14)(15)(16), substance abuse and UAI are cooccurring risk behaviors that may contribute to the HIV infection rates among MSM.
Over the past years, research studies have explored the association between substance abuse and other risk behaviors that might contribute to HIV infection in the MSM population (6,(15)(16)(17)(18)(19)(20). However, the results of these studies have been inconsistent on the significance of this association, previous metaanalyses on substance abuse among MSM or HIV infection failed to provide evidence of underlying differences in HIV-related risk behaviors and associated factors between substance abusers and non-users (21,22). Still, more evidence is needed. This quantitative review aimed to explore the risk factors associated with higher HIV/Syphilis infection rates among MSM substance abusers compared to the general MSM population. We focused on the sexual risk behaviors between substance abusers and non-users. Furthermore, understanding these issues could further facilitate effective intervention and prevention strategies among Chinese MSM.

. . Literature search strategy
This meta-analysis adhered to the PRISMA guidelines. We conducted a comprehensive search of PubMed, Web of Science, Embase, Scopus, Chinese National Knowledge Infrastructure, Chinese Wanfang Data, and VIP Chinese Journal Database for relevant studies with quantitative outcomes associated with HIV/Syphilis infection among men who have sex with men (MSM). And these articles published in English or Chinese between 2010 and May 31, 2022. Meta-analyses were performed to compare HIV and syphilis risks between substance abusers and non-users across studies.
An appropriate combination of keywords and the MeSH subject headings for the search, including (1) "men who have sex with men" OR "MSM" OR "gay man" OR "male homosexual" AND (2) ("HIV infection") OR "HIV"AND (3) "Club drug use" OR "Recreational drug use" OR "Illicit drug use" OR "Substance abuse." AND (4) "China." We also reviewed the bibliographies of included citations to identify references for consideration.

. . Inclusion and exclusion criteria
The inclusion criteria were as follows: (1) cross-sectional or longitudinal study design; (2) MSM as a target population; (3) the main outcome focus was HIV prevalence rate or HIV incidence; (4) reported the proportion of substance abuse among MSM in China; (5) were published in English or Chinese and conducted in China; (6) Sample sizes >50; (7) was a master or doctoral thesis which satisfied the above requirements.
Studies were excluded for the following reasons: (1) the study population was not MSM; (2) it exclusively focused on MSM living with HIV or substance abusers; (3) the studies without relevant quantitative data; (4) the study was a systematic review. The most comprehensive studies were included in the meta-analysis.

. . Study screening and data extraction
We imported the literature into Zotero to build a library, eliminated duplicates, and two authors (GH and ZT) screened the titles and abstracts for eligibility. According to the inclusion and exclusion criteria, two authors (CQ and ZT) conducted the full text screening. Discrepancies were discussed until agreement was reached, with an arbitrator (Gengfeng Fu) for unresolved disagreement.
Two authors (GH and ZT) used a standardized form for data extraction, including the following information: source (the primary author, publication year), study periods, sample size, study setting (city, state), recruitment strategy, survey methods, and recall . /fpubh. .
window; types and proportion of substances abused; population characteristics (e.g., sexual risk behaviors including unprotected anal intercourse, the number of male sexual partners, engaging in commercial sex or group sex); the proportion of reporting HIVpositive and syphilis-positive. All abstracted data were used to calculate prevalence rate ratios and relative risk.

. . Quality assessment
We used the Quality Assessment Checklist (QATSO score) (23) for quality assessment. This checklist is a validated quality assessment tool for HIV prevalence/risk behaviors among MSM (the checklist is provided in Supplementary material). The scoring system was based on five items: (1) Whether the sampling method is representative of the population of the study; (2) the measurement of the HIV objective (if the article is focusing only on risk behavior among MSM); (3) Whether response rate is reported in studies; (4) Whether confounding bias is controlled (such as stratification/matching/restriction/adjustment) when analyzing the associations; (5) Whether privacy or the sensitive nature of HIV is considered when conducting the survey. According to these quality items, the scores are 1, 0, and NA, representing "yes, " "no, " and "not applicable, " respectively. All scores were categorized into poor (0%−32%), satisfactory (33%−66%), and good (67%−100%) groups. Quality assessment scores are provided in Supplementary material.

. . Statistical analysis
Meta-analysis was performed using R software and was stratified by study design. We used a random -effects model to aggregate every outcome and estimated the pooled association between substance abuse and HIV infection and their 95% CI. Q statistics defined the heterogeneity between studies. Based on the I 2 classification suggested by Higgins and Thompson, we used the cutoff of 25, 50, and 75% to define as low, medium, and high levels of heterogeneity, respectively. If significant homogeneity was detected (I 2 > 50%), random effect models were employed to calculate the pooled effect rates and OR, otherwise, fixed effects models were employed.
Another subgroup analysis was performed to explore the sources of heterogeneity in these studies, such as sampling size, study periods, and study setting. Egger's regression test and the funnel plot evaluated the possible publication bias and the effect of small sample sizes. Finally, the sensitivity analysis was performed to explore the possible impact of abnormal or outlier data. We used R software (version 4.2.0) to conduct all statistical analyses.

. . Overview of studies
We identified 3,111 unique articles, 3,049 of which did not meet the inclusion criteria, and 62 articles progressed to full-text screening. Eventually, 52 eligible articles (including 61,719 MSM) were selected in this meta-analysis (7-9, 18-20, 24-69). The flow of the review process is shown in Figure 1.

. . Basic characteristics of the selected studies
All included papers contained 47 cross-sectional studies and 5 cohort studies. A total of 61,719 MSM was included across the included studies, with a maximum sample size of 6,710, a minimum sample size of 139, and 50 studies with more than 200 participants. The study location involved 24 cities and 11 provinces, and the sampling methods included peer referrals, snowball method, internet recruitment, voluntary counseling test, and venue-based mobilization. Five studies used voluntary counseling test (VCT) method to recruit MSM population, and seven studies used snowball sampling method to recruit participants. Other forty studies used more than one sampling methods to recruit participants. The survey methods were based on self-administrated questionnaires and a face-to-face interview. The characteristics of the studies selected for this review are summarized in Table 1.

. . Prevalence of HIV and syphilis
Of the 47 cross-sectional studies in the meta-analysis, 12 did not report HIV prevalence rates, and the other 35 used HIV ELISA testing to confirm HIV infection status. So we used data from the 35 studies to compare HIV prevalence rates among substances abusers .

. . Sensitivity analysis and publication bias
None of the individual study's results affected the pooled estimate odds ratio. ORs remained similar in the sensitivity analysis, which suggested that the results were stable and reliable.
Egger's test suggested no significant evidence of publication bias in comparing the prevalence of HIV (P = 0.51) between substance abusers and non-users (Figure 4).

. Discussion
We conducted a quantitative review in China to assess the HIV/syphilis epidemic and the correlation between these epidemics and substance abuse and other sexual risk behaviors .
/fpubh. .  among MSM in China. This meta-analysis provides insight into HIV transmission among substance abusers. It also provides an important suggestion for China's public health sector to develop more effective prevention and intervention strategies for the MSM population. We integrated and analyzed data from 52 studies and further validated that the prevalence of HIV or syphilis among substance abusers of Chinese MSM is significantly higher than the general MSM population, similar to previous results (17,22). We aggregated the characteristics, related sexual risk behaviors, and current HIV and syphilis status among Chinese MSM. We also identified the factors associated with HIV/syphilis infection between substance abusing MSM and non-users.
Our review showed a 23% (95% CI: 0.17-0.29) pooled proportion of Chinese MSM reported substance abuse, and in the past 6 months, a 25% (95% CI: 0.19-0.34) pooled proportion of Chinese MSM reported substance abuse. This finding is lower than the proportions reported among Chinese MSM in a global meta-analysis conducted in 2021 (P = 0.306, 95% CI: 0.238-0.373) (17). Furthermore, the pooled HIV prevalence was 10% among substance abusers, much higher than the HIV positivity rate in the general MSM population (P = 0.0507, 95% CI: 5.4%−6.1%) (2). The high HIV prevalence among substance-abusing Chinese MSM is a signal that, without effective intervention strategies, it may contribute to the HIV transmission risks among MSM will would lead to severe public health consequences. Our study results also showed that the substance abuse rate among Chinese MSM gradually increased over time. The proportion of substanceabusing MSM was about 19% (95% CI: 0.13-0.28) before 2018 and reached 27.0% (95%CI: 0.19-0.38) after 2018. One possible explanation for this phenomenon is that the rapid growth of the internet and the popularity of social media applications (such as Blued) have made MSM more susceptible to use substances. In recent years, a number of gay applications like Blued have been developed specifically for MSM social and sexual networking, increased used may facilitate seeking multiple sex partners (70, 71). Some applications targeting MSM have also emerged as important a venue through which MSM seek and maintain relationship with sex partners and substance abuse partners (72). The diversification of e-commerce platforms has provided convenient ways for MSM to obtain substances. It is worth noting that the rush popper and capsule zero were the most popular recreational drug among MSM. Although rush popper is banned or restricted in some countries like Canada and European Union (37), it is still not regulated as an illegal drug, and it can be easily obtained at a low cost online in China. In 2019, Chinese researchers investigated 2,616 MSM in six provinces through an online questionnaire (19). They found that 842 (32.2%) MSM had used at least one psychoactive substance, and 377 (14.4%) MSM reported using more than two psychoactive substances. For the MSM population, the rush poppers is still an important factor contributing to sexual behaviors, such as . /fpubh. .
increasing sexual desire and reducing sexual inhibition (18). MSM were more likely to seek casual sex partners and engage in UAI after using the drug. Moreover, rush poppers are believed to prolong erection which prolongs anal intercourse, thus increasing the likelihood of anal bleeding and the risk of HIV infection (29,65). It is strongly suggested that the public health sectors should pay attention to the issue of substance abuse, especially the rush poppers, and adopt targeted screening and detection for these subgroups of MSM.
Regarding the sexual risk behaviors among MSM, our study suggests that Chinese substance abusers were more likely to seek sex partners through the internet or gay applications than non-users in the last 6 months. These social media applications greatly facilitate the identification of sexual partners and do not have any restrictions on the time or location (70, 71). In addition, these applications also provide a platform for individuals to organize private parties where the combination of drug use and gay applications may contribute to an increase in the risk of HIV transmission among MSM (24).
Consistent with previous studies, our study suggests that substance abuse is associated with unprotected anal intercourse, commercial sex, and group sex (73)(74)(75). Similar results were reported by a United States study which found that substanceabusing MSM were twice more likely to have had commercial sex in the last 6 months than non-users (9). This result was lower than the 5.07 odds found in the study by Robert et al. abroad (76). The high level of sexual activity among substance abusers might make it more difficult to maintain a stable and regular sexual partner relationship. Drug abuse was positively associated with multiple sex partners during a sexual encounter (77,78), and unprotected sex encounter is more likely to occur during participation in group sex. Moreover, it has been demonstrated that the perianal skin is more susceptible to damage during unprotected anal intercourse and therefore provides optimal conditions for the transmission of HIV.
Alcohol consumption among MSM may also be a cause for concern although only five included papers provided information to compare substance abusers with non-users (6,45,51,62,73). Substance users were more likely to drink alcohol, and the combination of alcohol and drug use may reduce the sense of restraint and increase the sexual risk behaviors (15,49,51).
In our study, pooled HIV testing prevalence was higher among substance abusers than non-users. Substance abusers seem more likely to engage in high-risk sex behaviors (such as group sex, commercial sex, and unprotected anal intercourse) than non-users. Thus, they are more likely to use preventative methods, including frequent HIV and STI testing. The HIV and syphilis prevalence rates were higher among substance abusers than non-users, which suggested that MSM with a history of substance abuse were particularly more likely to develop HIV/syphilis infection. Compromised immunity due to syphilis infection may increase the risk of HIV acquisition and facilitate HIV transmission. Hence, screening and referral efforts for sexually transmissible infections are needed.
This meta-analysis is not without several limitations. First, as the cross-sectional surveys pooled together, it is difficult to infer the temporal sequence between substance abuse and HIV/Syphilis infection. Second, as respondents' drug abuse has not been confirmed by standardized laboratory testing, reporting bias and recall bias could affect the veracity of the results and thus underestimate the HIV prevalence of MSM. Third, some studies included in this meta-analysis used convenient samples or a crosssectional design. The resulting selection bias may have affected the veracity of our results. Moreover, for a lack of surveys from rural areas, we could not further explore the impact of substance abuse on the infection of HIV/Syphilis among all Chinese MSM.

. Conclusion
This study highlights the correlation between substance abuse and HIV/Syphilis infection. Substance abuse among the MSM population can increase the rate of high-risk sexual behaviors and facilitate HIV/Syphilis infection. The mechanism still needs to be explored and strengthened. Targeted knowledge promotion and expanding diagnostics interventions among high at-risk populations should be adopted for HIV/Syphilis prevention. Meanwhile, care providers should pay attention to substance abusers and related high-risk behaviors and encourage safe sex practices. Moreover, intervention programmers should utilize internet-based social organizations to provide peer education and implement social discrimination and HIV-related stigma reduction interventions to help slow the spread of HIV/Syphilis.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

Author contributions
HL, XG, and GF contributed to the manuscript's conception, design, and review. GC and TZ carried out the data collection and drafted the first manuscript. TZ and CS performed the statistical analysis. All authors contributed to the manuscript revision and approved the submitted version.